title: A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors.
abstract: BACKGROUND
  PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887.
  
  
  RESULTS
  Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity.
  
  
  METHODS
  Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated.
  
  
  CONCLUSIONS
  PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.
authors.affiliation: Universite Paris XI, Service des Innovations Therapeutiques Precoces (SITEP), Departement de Medecine, Institut Gustave Roussy, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: D Alan
authors.initials: DA
authors.lastname: Anthoney
authors.forename: A
authors.initials: A
authors.lastname: Proctor
authors.forename: Angela
authors.initials: A
authors.lastname: Scaburri
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Pacciarini
authors.forename: Bernard
authors.initials: B
authors.lastname: Laffranchi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pellizzoni
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: Rastilav
authors.initials: R
authors.lastname: Balheda
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Twelves
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D015331:Cohort Studies; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C549971:N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases